DEATH FROM ACUTE PANCREATITIS: M.R.C. Multicentre Trial of Glucagon and Aprotinin
Abstract
The influence of glucagon and aprotinin ('Trasylol') on the death-rate of acute pancreatitis has been studied in a randomised double-blind multicentre trial. The death-rate in 257 patients was 11%. In the doses used neither drug was found to diminish the risk of death.
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Cited by (129)
Pharmacological Management of Acute and Chronic Pancreatitis
2022, Comprehensive PharmacologyPancreatitis is often categorized as acute and chronic pancreatitis. Acute pancreatitis (AP) is an inflammatory condition that often results in a significant systemic inflammatory response; chronic pancreatitis (CP) is an ongoing inflammatory and fibrotic condition that often results in loss of exocrine and endocrine functions. Many pharmaceutical therapies have been trialed in pancreatitis. However, evidence based recommendations are limited by a paucity of large, randomized controlled studies and significant heterogeneity in available studies. In AP, early, aggressive fluid therapy is the most supported intervention. Therapies aimed at decreasing pancreatic stimulation (anti-secretory agents), inflammation (protease inhibitors, NSAIDs, glutamine), or oxidative stress (antioxidants, N-acetylcysteine, vitamin C, selenium) have also been used. Antibiotics and probiotics have also been used in AP. In CP, pharmaceutical therapies are often aimed at treating the resulting exocrine insufficiency, and there are several pancreatic enzyme replacement therapies (PERT) available. Pharmaceutical therapies are also used to treat the chronic pain that frequently accompanies CP. These therapies include non-opioid and opioid pain medications, along with adjuvant therapies (pregabalin, antidepressants, and ketamine) aimed at addressing the neuropathic component of CP pain. Therapies targeting decreasing pancreatic stimulation (PERT and octreotide) and inflammation (antioxidants) have also been used in CP.
Treatment of acute pancreatitis: An attempted historical review
2010, PancreatologyThis attempt at a historical review of the treatment of acute pancreatitis summarizes the findings of studies carried out in decades long past and shows their impact on the therapy of this disease today. It identifies in retrospect the correct avenues of research and the blind alleys, and describes the ebb and flow of interest in various forms of management. Acquaintance with the work of previous investigators may prevent the unnecessary rediscovery of old principles of treatment. Not all of the studies discussed can be found with search engines: they come from the author's personal library, collected over his 40 years as an active pancreatologist, and from the knowledge of the early literature bequeathed to him by his teachers and mentors.
The Clinical Problem of Biliary Acute Necrotizing Pancreatitis: Epidemiology, Pathophysiology, and Diagnosis of Biliary Necrotizing Pancreatitis
2001, Journal of Gastrointestinal SurgeryThe scientific basis of medical therapy of acute pancreatitis: Could it work, and is there a role for lexipafant?
1999, Gastroenterology Clinics of North AmericaFor a 30-year period beginning in 1958, the general basis of medical therapy of acute pancreatitis (AP) had as its focus the provision of supplementary antiprotease therapy usually given intravenously. This concept had its basis in the belief that the body's natural antiprotease defense mechanism, which relies heavily on α2-macroglobulin, together with α1-antiprotease (α1-antitrypsin), was inadequate to cope with the vast enzyme release that occurred with the onset of the more severe forms of the disease. Few studies have monitored the levels of α2-macroglobulin, and those that have usually demonstrate an early fall in the levels of this large molecule, which has the capacity to engulf two free trypsin molecules with a consequential stearic change in the shape of α2-macroglobulin. This change in configuration is recognized by the reticuloendothelial system resulting in a short half-life at around 15 minutes for the complexed molecule. The consumption of α2-macroglobulin results in a falling level over the first 5 days of illness with a gradual increase thereafter.22 It therefore tends to mirror the pattern of platelet response, and the extremely low levels found particularly in canine experimental work have not been shown to occur in clinical AP. This finding probably explains the failure of varying doses of intravenous aprotinin (Trasylol) as well as gabexate mesilate in large double-blind, randomized clinical studies.2, 13 Fresh-frozen plasma was at one time thought to be a better therapy then either aprotinin or gabexate mesilate, but the clinical trials of different dosages failed to verify any benefit for this substance.18, 19 As a result of these clinical studies, clinicians became disillusioned that application of such substances could benefit patients with severe AP.
Agents that minimize pancreatic secretion have also proven nonbeneficial, and clinical trials using glucagon, somatastatin, or its synthetic analogue octreotide6, 20, 23, 29 have shown no benefit. Aprotinin has been tried in different dosages given intravenously and has been used by the intraperitoneal route with no advantage to the patients treated in this fashion.17 British clinical studies tend to discount the possibility of such an approach bringing great benefit for patients.
The large double-blind, randomized multicenter study carried out in Germany and Switzerland examining the potential use of subcutaneous octreotide in a dose of 300 to 600 μg/d28 supported an earlier study carried out by the authors' group in Glasgow,20 which found no advantage in an even higher dose given intravenously by an approach similar to that used in the management of bleeding esophageal gastric varices. This study randomized 58 patients, all with objective evidence of severe AP, and no benefit from the treatment could be identified. The results of the German-Swiss combined study involving 300 patients with severe AP was similarly disappointing in terms of both mortality and morbidity.
Against this background a new theory emerged in the late 1980s, which reckoned that cytokines, chemokines, and leukotrienes released from leukocytes in response to the initial phase of AP were the explanation for the systemic inflammatory response syndrome, which is a feature of the disease. Rindernecht12 presented this idea in 1988, and it has become increasingly clear from a considerable body of experimental work and early clinical studies that multiple cascades of proinflammatory agents, such as interleukin (IL)-1, IL-2, IL-6, and IL-8, play important roles in the systemic effects of AP.3, 9, 10, 24, 25, 26
Other important factors include tumor necrosis factor (TNF)4, 5, 12 and platelet-activating factor (PAF).7, 8, 16 Thus, blocking of an individual proinflammatory cytokine, leukotriene, or chemokine may be helpful in the treatment of clinical AP either as a single agent or possibly combined with the enhancement of the anti-inflammatory effect of IL-10. The probability of a single agent having a profound effect on the clinical disease that is already established by the time the patient has reached the hospital seemed remote, but the initial clinical trials of the FAF antagonist lexipafant have shown an encouraging trend of results that may lead to much more effective therapy in the future.14, 15, 21 Although the various cascade systems have still to be fully unraveled, it is obviously possible that certain agents within the cascade have a more pivotal role than others, and much attention has focused on both TNF and PAF as possible candidates for such a pivotal role.
Examining the potential importance of PAF, the administration of the PAF antagonist lexipafant (all PAF antagonist drugs are identifiable by the suffix pafant) after the insult causing experimental AP proved beneficial,8 and this was the stimulus to clinical trials of lexipafant in the United Kingdom beginning in 1994. More recently, acceleration of the breakdown of PAF by a synthetic PAF acetyl hydrolase considerably improved the systemic effects of a severe form of AP in the opossum when the disease process had been in progress for 48 hours.11 Such experimental studies indicate that PAF may have a pivotal role in experimental AP.
Acute pancreatitis: Genetic risk and clinical implications
2021, Journal of Clinical MedicinePharmacological interventions for acute pancreatitis
2017, Cochrane Database of Systematic Reviews